As an agent having an effect of inhibiting the secretion of gastric acid, OMP is now being used to treat ulcers. However, as OMP itself is quite vulnerable to moisture, temperature, organic solvent, and pH, it is publicly known that its preparation is liable to be easily decomposed and/or transformed.
For example, it is reported that as for the OMP stability in pH, its rapid decomposition occurs in pH less than 4.0; a half life in neutral is about 14 hrs and it is very stable at more than 7.0 (Pilbrant and Cederberg, Scand. J. Gastroenterology, 1985: 20 (Suppl. 108) P113-120.
The acidic decomposition of OMP may be explained by acid-catalyzed rearrangement (G. Rackur et al., Biochem. Biophys. Res. Commun. 1985: 128(1). P477-484). It is reported that with the progress of decomposition, its decomposing rate has been on the drastic increase.
As mentioned in the above, OMP has recognized some disadvantages in that 1) since OMP is easily decomposed by acid or moisture, the manufacture of injectable suspension is not available b) decomposition or transformation is liable to occur under the normal pH of stomach. To cope with this problem, the enteric coated OMP is now being manufactured so as to demonstrate its efficacy in the small intestine, a target area, by maintaining the stabilized condition in oral administration tract.
The present manufacturing process of OMP in a form of enteric coating was suggested in Pilbrant and Cederberg, Scand. J. Gastroenterology, 1985: 20 (Suppl. 108), P113-120. However, it is reported that although said enteric coating has an stability suitable for the study of clinical trials, its long-term stability for storing proves to be reduced.
Also, German Laid-Open patent No. DE-A1-3046559 specified a manufacturing process of OMP in a form of water-soluble endothelial layer coating and secondary enteric coating, but the release of OMP in the small intestine proved not to be effective.
Also, German Laid-Open patent DE-A1-1204363 specified a 3-layer coating process: a) the 1st layer being coated with surface membrane, soluble in gastric juice and insoluble in intestinal juice b) the 2nd layer being coated with water-soluble surface membrane and c) the 3rd layer being an enteric coating. However, the preparation based upon said structure has recognized some disadvantages in that the release of OMP in the small intestine is not rapid and its formulation process is very complicated.
English Patent Applications Nos. 8610572 and 8610573 specified the manufacturing process of stabilized OMP; after adding a stabilizer into OMP to form a core, coating it with water-soluble endothelia layer, and finally, forming the enteric coating.
As far as said method is concerned, the following materials are used for stabilizing: sodium phosphate, citric acid aluminum, mixed aluminum/magnesium oxide, etc. In this method the manufacturing process is very complicated and the desirable stability cannot be obtained.
When OMP preparation is orally administered, it is easily decomposed and transformed under the normal pH of stomach; especially, an enteric coated OMP preparation requires more prolonged time in arriving at the effective serum concentration; an abnormal GI-tract motility may occur and in a concurrent administration with another drug, any exceptional serum concentration may also appear. To prevent the above disadvantages and to demonstrate a rapid absorption efficacy, therefore, a dosage form of OMP through a new administration route is necessary. In an animal experiment using the oral preparation, the possibility on the occurrence of tumor of the stomach is already reported and its long-term intaking might open the pyrolus owing to the enhanced pH in stomach.
To duly cope with the existing disadvantages as above, the inventor has conducted intensive study. With a notion that the pH in the rectum maintains a natural and/or weak alkaline in a range of 7.0, the inventor has succeeded in making said compositions administered to rectum, which may use the absorption of rectal membrane and using by a soluble basic amino acid as stabilizer, said compositions can be stabilized for a prolonged period.
Accordingly, the object of this invention, which differs from the existing ones in an administration route, is to provide stabilized OMp compositions designed for administration in rectum, demonstrating its efficacy through rectum's absorption.